This research grant addresses the significant health issue of pancreatic cancer demonstrated by the Program Announcement issued by the NIH (PA-05-116; Pilot Studies in Pancreatic Cancer). Pancreatic cancer will be responsible for over 31,000 deaths in the United States in 2005, making it the fourth most common cause of cancer-related death. It remains the most lethal cancer with 98% of people succumbing to the disease. Clearly, innovative research into the treatment of pancreatic cancer must be conducted if any progress is to be made in this under-studied, malignancy. The overall goal of the current grant proposal is to determine the most effective method of combining a new biologic therapy that targets the AKT serine/threonine kinase protein with standard chemotherapy. We have previously demonstrated that AKT is constitutively activate in 60% of human pancreatic tumors (Br. J Cancer, 89:2110, 2003). Furthermore, inhibition of AKT has little effect on pancreatic cancer cells, though cells became more sensitive to the cytotoxic effect of the chemotherapy gemcitabine (Br. J. Cancer, 89:391, 2003). Unfortunately, inhibition of AKT in these preliminary studies has used methods that cannot be adapted to treatment of patients (ie. siRNA, dominant negative constructs, PI3-kinase inhibitors that are toxic in animal studies, etc.) and therefore the utility of this novel targeted approach has been limited to experimental models. Fortunately, Abbott Laboratories has developed a novel AKT inhibitor that is specific and well-tolerated in animal models. We have conducted preliminary studies of these novel AKT inhibitors and confirmed specific inhibition of AKT in pancreatic cancer cell lines. The specific aims of the current grant proposal are: 1) to identify markers that predict sensitivity to these novel AKT inhibitors, 2) to determine whether AKT inhibition is effective in combination with diverse chemotherapies, and 3) to determine the in vivo efficacy of AKT inhibition in a xenograft model. The research methods will utilize both in vitro and in vivo models of pancreatic cancer to examine combining AKT inhibition with standard chemotherapies by analysis of variables such as: 1) molecular markers predictive of response, 2) diverse chemotherapies with divergent mechanisms, and 3) sequence of administration. These results will provide mechanistic as well as pre-clinical data in support of our hypothesis and will allow for the development of novel therapy of human pancreatic cancer. [unreadable] [unreadable] [unreadable]